High Rate Of Microsatellite Instability Research Articles

Gastric cancer is associated with a high rate of microsatellite instability versus chronic gastritis: A retrospective study

Abstract Objective: Microsatellite instability (MSI) in gastric cancer contributes to genetic complexities of gastric cancer. In the current study, we employed a panel of mononucleotide and dinucleotide markers to detect MSI in 99 gastric cancer patients and 91 chronic gastritis patients and further analyzed the association of MSI with clinicopathologic variables of the study patients. Methods: We retrospectively analyzed the clinicopathologic data of primary gastric cancer patients and chronic gastritis patients. MSI was analyzed using five microsatellite markers, including D2S12, D5S346, D17S799, BAT26, and D18S34. MSI was defined as either a band shift or the appearance of a novel band in DNA. Multivariate logistic regression analysis was used to predict risk of MSI. Results: Seventeen (17.2%) gastric cancer patients and 7 (7.7%) chronic gastritis patients were positive for MSI (P=0.012). Multivariate analysis further showed that gastric cancer was associated with a significantly higher likelihood for MSI versus gastritis (OR 3.73; 95% CI 1.19, 11.72; P=0.024) while age, drinking or smoking was not associated with increased MSI. Conclusion: Gastric cancer is associated with a high rate of MSI. MSI should be further explored in future studies with a larger sample size for its role in gastric cancer development and as a predictive biomarker.

1041P - Clinical features and frequency of mismatch repair protein deficiency in ovarian clear cell and endometrioid carcinoma patients

BackgroundThe rates of mismatch repair (MMR) protein deficiency and microsatellite instability (MSI) in ovarian clear cell (CC) and endometrioid (EM) cancer patients were investigated. The clinical features of CC and EM were also analyzed. MethodsPatients postoperatively diagnosed as CC or EM carcinoma from January 2006 to December 2015 were eligible. Diagnosis of all cases was confirmed by the Central Pathological Review Board. MMR protein was analyzed by IHC using a monoclonal antibody and MSI was examined by a multiplex PCR assay for five microsatellite markers, BAT25, BAT26, NR-21, NR-24, and MONO-27. MLH1 IHC-negative cases were examined for DNA hypermethylation of the MLH1 promoter. ResultsWe enrolled 339 cases consisting of 219CC, 116 EM and 4 mixed type (MT) cases. One case could not be evaluated by IHC. MMR protein deficiency was confirmed in five CC (2.3%), 16 EM (13.9%) and 1MT case (25%). Deficiency was observed in 4 cases for MLH1 and PMS2, in 13 cases for MSH2 and MSH6, in 1 case for MSH2 and PMS2, in 2 cases for MSH6, and in 1 case for PMS2. DNA hypermethylation of the MLH1 promoter was detected in one of the four MLH1 and PMS2 deficiency cases. Three of the 339 cases could not be evaluated by MSI. A high rate of MSI was confirmed in 13 cases (3.9%) and MMR deficiency was detected by IHC in these cases. However, MSI was not detected in the other nine cases where MMR deficiency was detected by IHC. The median age of all 339 cases was 54 (CC 54, EM 51) and that of CC and EM cases with MMR deficiency was 39 and 48 years, respectively. ConclusionsThe rate of MMR deficiency in CC and EM was not high, whereas CC in young women was more frequent. IHC is a more successful screening method of MMR deficiency in ovarian CC and EM compared with MSI detection. The rate of MLH1 promoter hypermethylation (epigenetic MMR deficiency) in ovarian CC and EM was less than that of endometrial cancer. Legal entity responsible for the studyThe author. FundingNational Hospital Organization of Japan. DisclosureThe author has declared no conflicts of interest.

Gene mutations of SWI/SNF complex and molecular profile in colorectal cancer.

3600 Background: The SWI/SNF complex includes proteins produced by 29 genes that regulate chromatin structure remodeling through effects upon transcription, replication, and repair. Understanding how SWI/SNF gene mutations interact to affect cancer progression could lead to new treatment strategies. Methods: We analyzed 7,370 colorectal cancer (CRC) samples with immunohistochemical stains (IHC) and Next-Generation Sequencing (NGS) using a 592-gene panel to examine the association between gene mutations of the SWI/SNF complex ( ARID1A, ARID2, PBRM1, SMARCA4, SMARCB1, SMARCE1, BCL11A, BCL11B, BCL7A, SS18, and SS18L1) and molecular features. Results: The overall mutation rate of the SWI/SNF complex genes was 11.3% ( ARID1A: 7.7% , ARID2: 1.7% , SMARCA4: 1.3% , PBRM1: 1.2% , BCL11A: 1.0% , SMARCB1: 0.5% , BCL11B: 0.5% , SMARCE1: 0.3% , SS18: 0.3% , BCL7A: 0.1% , SS18L1: 0.1%). When compared to tumors with SWI/SNF wild-type genes, those tumors with SWI/SNF gene mutations showed significantly higher rates of microsatellite instability (MSI)-high (40.9% vs 2.4%, P < 0.001), tumor mutational burden (TMB)-high (>= 10mut/MB) (56.8% vs 21.6%, P < 0.001) and PD-L1 positivity (17.9% vs 5.5%, P < 0.001). Tumors with each gene mutant also had strong association with the immune profile (MSI-high, TMB-high, and PD-L1 positivity) (Table). Furthermore, even SWI/SNF gene mutant samples with microsatellite stable status were significantly associated with TMB-high (28.2%, P < 0.001) and PD-L1 positivity (10.0%, P < 0.001). Conclusions: Gene mutations of the SWI/SNF complex exhibit findings that suggest that this subgroup of CRCs may have a higher likelihood of response to PD-1 and PD-L1 targeting monoclonal antibodies. If validated in other data sets, these findings can be used to justify clinical trials with eligibility based upon the presence of mutations within the SWI/SNF complex. [Table: see text]

Comparative molecular analyses of left-sided colon, right-sided colon, and rectal cancers.

Tumor sidedness has emerged as an important prognostic and predictive factor in the treatment of colorectal cancer. Recent studies demonstrate that patients with advanced right-sided colon cancers have a worse prognosis than those with left-sided colon or rectal cancers, and these patient subgroups respond differently to biological therapies. Historically, management of patients with metastatic colon and rectal cancers has been similar, and colon and rectal cancer patients have been grouped together in large clinical trials. Clearly, the differences in molecular biology among right-sided colon, left-sided colon, and rectal cancers should be further studied in order to account for disparities in clinical outcomes. We profiled 10,570 colorectal tumors (of which 2,413 were identified as arising from the left colon, right colon, or rectum) using next-generation sequencing, immunohistochemistry, chromogenic in-situ hybridization, and fragment analysis (Caris Life Sciences, Phoenix, AZ). Right-sided colon cancers had higher rates of microsatellite instability, more frequent aberrant activation of the EGFR pathway including higher BRAF and PIK3CA mutation rates, and increased mutational burden compared to left-sided colon and rectal cancers. Rectal cancers had higher rates of TOPO1 expression and Her2/neu amplification compared to both left- and right-sided colon cancers. Molecular variations among right-sided colon, left-sided colon, and rectal tumors may contribute to differences in clinical behavior. The site of tumor origin (left colon, right colon, or rectum) should certainly be considered when selecting treatment regimens and stratifying patients for future clinical trials.

Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation.

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.

Small Bowel Adenocarcinoma as the Cause of Gastrointestinal Bleeding in Celiac Disease: A Rare Malignancy in a Common Disease.

Introduction. Celiac disease is associated with an increased risk of small bowel malignancies, particularly lymphoma. Its association with small bowel carcinoma is less known. Case Description. We report a case of an 89-year-old woman with celiac disease who experienced recurrent episodes of gastrointestinal bleeding and was ultimately found to have adenocarcinoma of the small intestine. Discussion and Evaluation. Diagnosis of small bowel adenocarcinoma is often delayed because of the need for specialized modalities, which are often deferred in the inpatient setting. Although resection is the modality of choice for small bowel tumors, a majority is either locally advanced or metastatic at diagnosis, and even localized cancers have worse prognosis than stage-matched colorectal tumors. The role of adjuvant chemotherapy is uncertain, but it is often offered extrapolating data from other gastrointestinal cancers. Small bowel carcinomas occurring in the context of celiac disease appear to be associated with higher rates of microsatellite instability than sporadic tumors, although other specific genomic abnormalities and mechanisms of carcinogenesis in celiac disease remain unknown. Conclusion. Recurrent episodes of gastrointestinal bleeding in a patient with celiac disease should prompt an early evaluation of the small bowel to assure timely diagnosis of carcinoma at an early curable stage.

The molecular background of mucinous carcinoma beyond MUC2.

The increasing interest of the oncology community in tumour classification and prediction of outcome to targeted therapies has put emphasis on an improved identification of tumour types. Colorectal mucinous adenocarcinoma (MC) is a subtype that is characterized by the presence of abundant extracellular mucin that comprises at least 50% of the tumour volume and is found in 10–15% of colorectal cancer patients. MC development is poorly understood, however, the distinct clinical and pathological presentation of MC suggests a deviant development and molecular background. In this review we identify common molecular and genetic alterations in colorectal MC. MC is characterized by a high rate of MUC2 expression. Mutation rates in the therapeutically important RAS/RAF/MAPK and PI3K/AKT pathways are significantly higher in MC compared with non‐mucinous adenocarcinoma. Furthermore, mucinous adenocarcinoma shows higher rates of microsatellite instability and is more frequently of the CpG island methylator phenotype. Although the majority of MCs arise from the large intestine, this subtype also develops in other organs, such as the stomach, pancreas, biliary tract, ovary, breast and lung. We compared findings from colorectal MC with tumour characteristics of MCs from other organs. In these organs, MCs show different mutation rates in the RAS/RAF/MAPK and PI3K/AKT pathways as well, but a common mucinous pathway cannot be identified. Identification of conditions and molecular aberrations that are associated with MC generates insight into the aetiology of this subtype and improves understanding of resistance to therapies.

Microsatellite instability status does not predict total lymph node or negative lymph node retrieval in stage III colon cancer

The relationship between higher total lymph node resection number in colorectal cancer resection specimens and improved overall survival is well known. Recent studies describe an association between a high rate of microsatellite instability and a high total lymph node count in colorectal cancer. Higher lymph node retrieval may potentially explain the improved survival seen in cancers with microsatellite instability. We investigate whether these associations can be validated in a cohort of American Joint Committee on Cancer stage III colon cancers. Medical records from 200 cases of stage III colon cancer resection specimens were reviewed, and sufficient tissue was available for 168. Expression of DNA mismatch repair proteins was determined by immunohistochemistry, and microsatellite status, by polymerase chain reaction. The mean total lymph node count in cases with microsatellite instability versus microsatellite stable tumors (15.9 versus 16.9; P = .664) and the mean number of negative lymph nodes in each respective category (12.2 versus 13.6; P = .522) were not significantly different. There was no difference between microsatellite stable cases and cases with microsatellite instability when total lymph node counts (P = .953) or negative lymph node counts (P = .381) were analyzed with respect to percentage of cases above and below the medians. This cohort of stage III colon cancers does not support a significant relationship between microsatellite status and a higher retrieval of total or negative lymph nodes. Although microsatellite instability is associated with improved overall survival in our cohort (P = .026), the reason for this does not appear to be related to higher numbers of retrieved lymph nodes.

Loss of Expression of DNA Mismatch Repair Proteins Is Rare in Pancreatic and Small Intestinal Neuroendocrine Tumors

Two recent studies have identified a high rate of microsatellite instability (MSI) in pancreatic neuroendocrine tumors (pNETs). Microsatellite instability is rare in small intestinal neuroendocrine tumors (NETs). It is unclear why there is discordance in the frequency of MSI in the 2 studies of pNETs and why this mechanism is comparatively rare in small intestinal tumors. Loss of expression of DNA mismatch repair (MMR) proteins, which is known to correlate strongly with MSI, is not well studied in pancreatic or small intestinal NETs. To determine if there is loss of expression of MMR protein expression in pancreatic or small intestinal NETs. Sixty-nine patients (31 male, 38 female; mean age, 59.2 years) were identified who had a resection for a primary pancreatic (n = 35) or primary small intestinal (n = 34) NET during an 18-year period. Immunohistochemical stains for MLH1, MSH2, MSH6, and PMS2 were applied to archived tissue from all cases. All pNETs with adequate tissue (n = 32) were also assessed by MSI analysis. There was preserved expression of MLH1, MSH2, MSH6, and PMS2 in all 35 pNETs. Of 32 pNETs tested by polymerase chain reaction, 28 were microsatellite stable and DNA did not amplify in 4. In 34 small intestinal NETs, 2 cases had indeterminate MLH1 and 1 case had indeterminate PMS2 expression. The remainder had intact MMR protein expression. Defects in DNA MMR proteins are rare in pancreatic and small intestinal NETs, raising doubt that MSI plays a significant role in the pathogenesis of these tumors.

Clinical Implications of Microsatellite Instability and MLH1 Gene Inactivation in Sporadic Insulinomas

The molecular pathogenesis of sporadic insulinomas is unknown. There is a lack of biomarker to distinguish benign and malignant form of insulinoma. Our objective was to confirm the occurrence of microsatellite instability (MSI) in insulinomas, to identify alterations of mismatch repair (MMR) genes in the tumors, and to evaluate the possibility to distinguish benign and malignant insulinoma or to predict the clinical outcome of patients with these alterations. We detected MSI and inactivation of MLH1 gene in 55 sporadic insulinomas by PCR, immunohistochemical staining, allelic typing, analysis of promoter methylation, and exon mutations. Their correlations with clinicopathological characteristics were analyzed with univariate and multivariate statistic analysis. A high rate of MSI (MSI-H) was found in 33% of sporadic insulinomas. Reduced expression of mutL homolog 1 (MLH1) protein was observed in 36% of insulinomas and correlated with MSI-H (P = 0.008). Promoter methylation and loss of heterozygosity of MLH1 gene was found in 31 and 49% of insulinomas, respectively. Reduced expression of MLH1 and MSI-H were significantly associated with both tumor malignancy (P = 0.033 and P = 4.8 x 10(-6), respectively) and incurable disease (P = 0.006 and P = 0.001, respectively). High frequency of MSI occurred in sporadic insulinomas. The silencing of MLH1 gene may partially contribute to the MSI-H in the tumors. Assessing MSI-H and expressions of MLH1 could be used to distinguish benign and malignant insulinomas and to predict the outcome of patients.

Polymorphism of the 5,10-Methylenetetrahydrofolate Reductase (MTHFR) Gene and Microsatellite Instability (MSI) in Mucinous Colorectal Cancer

Purpose: Generally, a mucinous carcinoma (Muc) of the colon show higher rates of microsatellite instability (MSI) than a non-mucinous carcinoma (non-Muc). Mutated methylenetetrahydrofolate reductase (MTHFR) brings about low enzyme activity, which may reduce genomic DNA methylation. These processes may be critical for the oncogenic transformation of human cells. We compared the relationship of MSI and MTHFR polymorphism in Muc to that in non-Muc. Methods: From March 2003 to August 2007, genomic DNA was isolated from whole blood and tissue specimens of 285 colorectal cancer patients (Muc: 31 cases, non-Muc: 254 cases) and 448 normal control patients. These were subjected to MSI analysis and MTHFR genotyping by using PCR-based restriction fragment length polymorphism analyses. Results: MSI was significantly more frequent in the Muc group (40.7%) than in the non- Muc group (14.8%). The frequencies of polymorphism of MTHFR 677C＞T were CC (31.5%), CT (57%), and TT (11.5%) in the patient group and 32.4%, 53.1%, and 14.5% in the control group. In the Muc group, the frequencies of polymorphism of MTHFR 677C＞T were CC (36%), CT (56%), TT (8%), and in the non-Muc group, they were 31.1%, 57%, and 11.9%. The frequencies of polymorphism of MTHFR 1298A＞C were AA (73%), AC (21.3%), and CC (5.7%) in the patient group and 69.6%, 28.6%, and 1.8% in the control group. In the Muc group, the frequencies of polymorphism of MTHFR 1298A＞C were AA (50%), AC (30%), and CC (20%), and in the non-Muc group, they were 76%, 20.3%, and 3.7%. The Muc group showed higher frequencies of the CC variant than the non-Muc group (P-value=0.018). No relation between MSI and MTHFR polymorphisms were seen in any comparison of the Muc and the non-Muc groups. Conclusions: The Muc group showed higher rates of MSI than the non-Muc group, but no definite difference between the Muc and the non-Muc groups was noted in the case of polymorphism of MTHFR 677C＞T. However, the TT-type variant showed slightly lower frequencies in the Muc group than in the non-Muc group. On the contrary, the Muc group showed a higher rate of the CC variant in polymorphism of MTHFR 1298A＞C. These inconsistent results seem to be due to the small size of the Muc group, so further study is needed.

Poorly differentiated colorectal adenocarcinomas show higher rates of microsatellite instability and promoter methylation of p16 and hMLH1: A study matched for T classification and tumor location

Extensive genetic and epigenetic analysis of poorly differentiated colorectal adenocarcinomas (Por) has been difficult, as the number of cases is too small. We investigated genetic and epigenetic alterations of 53 cases of Por and 53 cases of well-differentiated colorectal adenocarcinomas (WD) to clarify their differences. The cases of WD were matched with the cases of Por for T classification and tumor location, which influence genetic and epigenetic alterations. We evaluated microsatellite instability (MSI) status and loss of heterozygosity (LOH) of four loci (2p, 5q, 17p, 18q), and defined "MSI tumors" as those that showed MSI-H, and "chromosomal instability (CIN) tumors" as those that showed LOH but not MSI-H. Further, we evaluated the methylation status of the hMLH1 and p16 promoter region. MSI tumors were significantly more frequent in Por (22.6%) than in WD (3.8%; P = 0.0041). CIN tumors were significantly less frequent in Por (64.2%) than in WD (83.0%; P = 0.046). Further, methylation of the p16 and hMLH1 promoter region was significantly more frequent in Por than in WD (P = 0.037, P = 0.047, respectively). Our results indicate that Por tumorigenesis strongly correlates with MSI and methylation of the p16 and hMLH1 promoter region.

Mucinous carcinomas of the colon and rectum show higher rates of microsatellite instability and lower rates of chromosomal instability

The clinicopathologic significance of mucinous carcinomas (Muc) of the colon and rectum has been widely discussed, but there have been few studies on Muc regarding genetic and epigenetic alterations. The current study analyzed genetic and epigenetic alterations of Muc to clarify their differences from well differentiated adenocarcinomas (WD). Thirty-nine cases of Muc and 39 cases of WD were investigated. Cases of WD were matched with cases of Muc for T classification and tumor location. Microsatellite instability (MSI) status and loss of heterozygosity (LOH) of four loci (2p, 5q, 17p, 18q) were evaluated. The methylation status of the hMLH1 promoter region in Muc was also examined. "MSI tumors" were defined as those that showed MSI-high, and "chromosomal instability (CIN) tumors" were defined as those that showed LOH but not MSI-high. MSI tumors were significantly more frequent in Muc (30.8%) than in WD (5.1%). CIN tumors were significantly less frequent in Muc (53.8%) than in WD (87.2%). In Muc, MSI tumors were significantly more frequent in the proximal colon (55.6%) than in the distal colon (9.5%). Also, methylation of the hMLH1 promoter region in Muc was significantly more frequent in MSI tumors (83.3%) than in CIN tumors (27.8%) (P = 0.0077). When matched for T classification and tumor location, Muc shows higher rates of MSI and lower rates of CIN than WD.. Muc shows different characteristics according to tumor location, and methylation of the hMLH1 promoter region strongly correlates with Muc tumors showing MSI.

Microsatellite instability in gastric MALT lymphoma

The role of microsatellite instability and defects in DNA mismatch repair mechanism in the pathogenesis of gastric lymphoma of mucosa-associated lymphoid tissue (MALT) type is still controversial, as both negative and positive findings have been reported. This may be explained mainly by arbitrary selection of the tested loci, the use of various techniques of microsatellite instability analysis and by different definitions of replication error positive phenotype. The aim of our study was to evaluate the instability at selected microsatellite markers using the GeneScan Analysis Software. DNA from paraffin-embedded tissue blocks of 13 previously untreated patients with localized gastric MALT lymphoma was extracted. Five microsatellite markers, which are located in hMSH2, hMLH1, P16, APC and MLL loci, were selected from the genetic database. We found genetic instability in tumors of 9/13 patients with gastric MALT lymphoma (69%). Seven of them had replication-error-positive phenotype (54%). Microsatellite instability was found in 39% of the samples in the MLL locus, 39% in the APC, 46% in the P16, 23% in the hMLH1 and none in the hMSH2. This study demonstrates that microsatellite instability has more prominent role in pathogenesis of gastric MALT lymphoma than reported to date. We suggest that microsatellite instability should be analyzed with markers adjacent to chromosomal loci that are involved in lymphomas. Our findings support the ‘Real Common Target genes’ theory of high rate of microsatellite instability in specific genes, which are associated with related tumors.

Allelic Imbalance of 8p Indicates Poor Survival in Gastric Cancer

Gastric cancer is a common tumor worldwide and a tremendous health burden. However, the underlying mechanisms of tumorigenesis in this cancer's development are primarily undefined. Allelic imbalance (AI) of 8p has been reported in many cancers, yet, the target(s) of alteration and the importance of allelic imbalance on this chromosomal arm in gastric carcinoma development remained to be characterized. Our findings confirmed a high rate of AI on 8p in gastric cancers. Moreover, we demonstrated that AI on 8p, either overall or at marker D8S560, was associated with poorer survival in patients with gastric cancer. Finally, gastric cancers with a high rate of microsatellite instability were significantly associated with noncardia tumors and with female gender.

Age related microsatellite instability in T cells from healthy individuals

Many immune functions decline with age and may jeopardize the elderly, as illustrated, for example by the significantly higher mortality rate from influenza in old age. Although innate and humoral immunity are affected by aging, it is the T cell compartment, which manifests most alterations. The mechanisms behind these alterations are still unclear, and several explanations have been offered including thymic involution and Telomere attrition leading to cell senescence. Age related accumulation of mutations has been documented and could serve as an additional mechanism of T cell dysfunction. One effective repair mechanism capable of rectifying errors in DNA replications is the mismatch repair (MMR) system. We previously reported a comparative examination of individual DNA samples from blood cells obtained at 10 year intervals from young and old subjects. We showed significantly higher rates of microsatellite instability (MSI), an indicator of MMR dysfunction in older subjects, compared to young. In the present study we confirm this result, using direct automated sequencing and in addition, we demonstrate that as CD8 lymphocytes from aged individuals, undergo repeated population doublings (PDs) in culture, they develop MSI. CD4 clones that also undergo repeated PDs in culture develop significant MSI as well. Elucidation of this previously unexplored facet of lymphocyte dynamics in relation to aging may help identify novel mechanisms of immunosenescence and pathways that could serve as targets for interventions to restore immune function.

2 Tumor Suppressor Genes and Human Cancer

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.

Microsatellite instability in primary neoplasms from HIV+ patients

AIDS is associated with a high risk of certain malignancies, notably Kaposi's sarcoma (KS) and B-cell non-Hodgkin's lymphoma (NHL). The pathogenesis of these malignancies is not fully understood. One mechanism of malignant transformation recently described in colon tumorigenesis results from defects in DNA mismatch repair, manifest as widespread microsatellite instability. We demonstrate a high rate of microsatellite instability in KS and aggressive lymphomas obtained from HIV-infected patients, whereas there is no evidence of instability in similar lesions from HIV-negative patients. Further elucidation of the underlying mechanisms responsible for HIV-associated instability in primary tumours may provide insight into the pathogenesis of these AIDS-related neoplasms.